NK Cells Mediate a Crucial Graft-versus-Leukemia Effect in Haploidentical-HSCT to Cure High-Risk Acute Leukemia

• Published in: Trends in immunology 2018-07, Vol.39 (7), p.577-590
• Main Authors: Locatelli, Franco, Pende, Daniela, Falco, Michela, Della Chiesa, Mariella, Moretta, Alessandro, Moretta, Lorenzo
• Format: Article
• Language: English
• Subjects: Antigens; Cancer; Cytomegalovirus; Genes; Genetic engineering; Graft vs Leukemia Effect - immunology; Graft-versus-host reaction; Graft-versus-leukemia reaction; Grafting; Hematology; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Histocompatibility antigen HLA; HLA Antigens - immunology; Humans; Immunoglobulin-like receptors; Killer Cells, Natural - immunology; Leukemia; Leukemia - immunology; Ligands; Lymphocytes; Lymphocytes B; Lymphocytes T; Molecular chains; Natural killer cells; NKG2 antigen; Prophylaxis; Receptor mechanisms; Receptors; Stem cell transplantation; T cell receptors; Transplantation; Tumors; Viruses
• ISSN: 1471-4906; 1471-4981
• DOI: 10.1016/j.it.2018.04.009

Natural killer (NK) cells are involved in innate defenses against viruses and tumors. Their function is finely tuned by activating and inhibitory receptors. Among the latter, killer immunoglobulin-like receptors and CD94/NKG2A recognize human leukocyte antigen (HLA) Class I molecules, allowing NK cells to discriminate between normal and aberrant cells, as well as to recognize allogeneic cells, because of their ability to sense HLA polymorphisms. This latter phenomenon plays a key role in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for high-risk acute leukemia patients transplanted from an NK-alloreactive donor. Different haplo-HSCT settings have been developed, either T depleted or T replete – the latter requiring graft-versus-host disease prophylaxis. A novel graft manipulation, based on depletion of αβ T cells and B cells, allows infusion of fully mature, including alloreactive, NK cells. The excellent patient clinical outcome underscores the importance of these innate cells in cancer therapy. T cell-depleted haplo-identical HSCT represents a novel approach based on grafts depleted of αβT and B cells. This method allows the prompt availability of potent effector cells (i.e., NK and γδT cells), capable of preventing leukemia relapse and controlling infections. KIR-mediated recognition of epitopes shared by HLA Class I alleles is the basis for the NK alloreactivity, which is crucial for the graft-versus-leukemia effect and prevention of graft-versus-host disease in T cell-depleted haplo-HSCT. CMV infection/reactivation drives the expansion of adaptive NK cell subsets displaying specialized effector function and long-term persistence. These cells may be harnessed as immunotherapeutic tools. NK cells may represent a suitable platform for novel therapeutic approaches, such as CAR-engineered NK cells. In addition, the use of monoclonal antibodies against inhibitory checkpoints may unleash antitumor NK cell function.